It has been known that noradrenaline and adrenaline have various activities on nerves or smooth muscles and the like as neurotransmitters and hormones present in a living body. Thus, adrenergic receptors which are responsive to such neurotransmitters/hormones via binding are considered to be target molecules for various drug compounds that are therapeutically important.
Adrenergic receptor belongs to a G-protein coupled receptor family and is classified into three subfamilies, i.e., α1, α2 and β adrenergic receptor. It is known that all the subfamilies of adrenergic receptor are activated by binding with noradrenaline and adrenaline, but different cellular signal transduction mechanisms are employed thereafter. It is demonstrated that increase in calcium ion is caused by α1 adrenergic receptor, inhibition of an adenylyl cyclase is caused by α2 adrenergic receptor, and stimulation of an adenylyl cyclase is mostly caused by β adrenergic receptor (for example, see Non-Patent Document 1).
Thus, the physiological mechanism of activation is different for each subfamily described above. For example, β adrenergic receptor subfamilies are further classified into three classes, i.e., β1, β2 and β3. With respect to these, it is recognized that stimulation of β1 adrenergic receptor causes an increase in heart rate and stimulation of β2 adrenergic receptor causes a relaxation of the smooth muscle tissue, especially resulting in lower the blood pressure when vascular smooth muscle tissue is relaxed.
It is also reported that β3 adrenergic receptor is present in adipocyte, brain, gallbladder, prostate, gut and the like. Thus, it is believed that β3 adrenergic receptor agonist activity is useful as an agent for prevention and treatment of diabetes, obesity, hyperlipidemia, depression, biliary stone, a disorder derived from hyperactivity of biliary tract or a disorder derived from hyperactivity of digestive tract, or a disorder derived from decreased tear secretion, etc. (for example, see Non-Patent Documents No. 2 to 9 and Patent Documents No. 1 and 2).
It was also shown that β3 adrenergic receptor is expressed in urinary bladder smooth muscle and, with the stimulation of β3 adrenergic receptor, relaxation of the urinary bladder smooth muscle is caused (for example, see Non-Patent Documents No. 10 and 11). Thus, it is expected that an agonist of β3 adrenergic receptor is useful as an agent for prevention or treatment of frequent urination or urinary incontinence, which occurs in overactive bladder.
Meanwhile, with regard to α1 adrenergic receptor, which is other subfamily of the adrenergic receptor, it is reported that the receptor is expressed in vas deferens, submaxillary gland, kidney, spleen, liver, aorta, prostate, urinary tract and the like in rats. Further, a certain type of selective antagonists of the receptor has been used for the treatment of benign prostatic hyperplasia (for example, see Non-Patent Documents No. 1 and 13).
In this regard, agonists of α1 adrenergic receptor, for example, phenylephrine, methoxamine, metaraminol, midodrine, etc., are known to have an activity of increasing blood pressure by contracting blood vessels, and therefore used as hypertensors (see, for example, Non-Patent Document 12). Further, in Non-Patent Document 12, relationship between selective activation of α1 adrenergic receptor subtype and urinary incontinence is discussed. Specifically, the α1 adrenergic receptor is classified into subtypes of α1A, α1B, α1D, etc., and among these, the α1A subtype is expected to be useful for prevention or treatment of stress incontinence based on its activity of contracting a urinary bladder neck or urethral smooth muscles.
As it is evident from the above descriptions, when agonists or antagonists which bind to an adrenergic receptor are used for treatment of a certain disorder under specific purpose, generally it is preferable to consider their selectivity for receptor subfamily, in particular their selectivity for subtype. In particular, when an agonist of β3 adrenergic receptor is used under the purpose of treating diabetes, obesity, hyperlipidemia, depression, biliary stone, a disorder derived from hyperactivity of biliary tract, a disorder derived from hyperactivity of digestive tract, frequent urination or urine incontinence derived from overactive bladder, or a disorder derived from decreased tear secretion, etc., an agonist which has high selectivity for the subtype of β3 adrenergic receptor is generally selected and used. As described above, there can be also a case in which stimulation of β1 and β2 adrenergic receptor subtypes may cause increased heart rate or low blood pressure, that can be undesirable for certain patients.
Similarly, it is preferable that stimulation of α1 adrenergic receptor as other subfamily is also considered as a factor which may also cause a secondary physiological reaction in blood vessels of peripheral tissues, etc. of certain patients, although it is not originally intended.
In the Patent Documents No. 3 to 5, a specific kind of compound having β3 adrenergic receptor agonist activity is disclosed [i.e., the compounds of the Formula (4) to (6) shown below]. However, the compounds of the present invention are not disclosed in any of prior art documents.
Formula (4) that is described in Patent Document 3:

Formula (5) that is described in Patent Document 4:

Formula (6) that is described in Patent Document 5:

Furthermore, Patent Documents No. 3 to 5 include no descriptions regarding selective stimulation of β3 adrenergic receptor compared to stimulation of α1 adrenergic receptor.